Spherical particles used as raw materials of pharmaceuticals have been mainly used as seeds of sustained-release preparations and enteric coated preparations. Examples of such spherical particles for pharmaceutical use include "Sugar Spheres" made mainly of sucrose/corn starch, which is prescribed in the "National Formulary (NF)"; and purified sucrose spheres (e.g., "Nonpareil-103", a tradename of Freund Industrial Co., Ltd.), sucrose/starch spheres (e.g., "Nonpareil-101", a tradename of Freund Industrial Co., Ltd.) and microcrystalline cellulose spheres (e.g., "Celphere" made by Asahi Chemical Industry Co., Ltd.), which are prescribed in the Japanese Pharmaceutical Excipients (JPE 1998).
All of the substances serving as the raw materials of such spherical particles have physiochemical properties suited for the formation of spherical shapes. For example, a series of commercial products sold under the aforementioned tradename "Nonpareil.RTM.", which have cores made of granulated sugar having an octahedral to dodecahedral monoclinic crystalline structure, are suitable for the sphere formation, because they can also effectively act as binders in the form of aqueous solutions. Commercial product sold under the aforementioned tradename "Celphere.RTM.", which is a spherical particle without a core, can also be formed into spheres readily, because the raw component crystalline cellulose thereof has a short fibrous form.
The commercial product "Nonpareil-103.RTM.", for example, is known to be produced by charging granulated sugar as a core into a centrifugal tumbling apparatus (e.g., "CF-Granulator" manufactured by Freund Industrial Co., Ltd.; hereinafter, simply referred to as "CF apparatus"), dispersing sucrose microparticles or powders over the granulated sugar core while spraying an aqueous sucrose solution as a binder on the core to thereby coat the granulated sugar with sucrose, and then granulating the resultant coated granulated sugar into spheres. Thus, the product "Nonpareil-103.RTM." can be said to consist of 100% sucrose, since granulated sugar has the same chemical composition as that of sucrose.
The commercial product "Nonpareil-101.RTM." is known to be produced by charging granulated sugar as a core into CF apparatus, dispersing microparticles or powders of a sucrose/starch mixture over the granulated sugar core while spraying an aqueous solution of a sucrose/starch mixture as a binder on the core to thereby coat the granulated sugar with the sucrose/starch mixture, and then granulating the resultant coated granulated sugar into spheres. In the product "Nonpareil-103.RTM.", the content ratio of sucrose to starch is 65-85%:35-15%.
Another type of spherical particle granulated from a core and the method for the production thereof is disclosed in Japanese Patent Application Laid-open No. 5-229961, in which the spherical particle comprises a mixture of a water-soluble substance (e.g., lactose) and a water-insoluble substance (e.g., cellulose) and has a particle diameter of 0.1-1 mm.
These spherical particles can be used for pharmaceutical preparation. However, many medicinal agents often react with the raw substances of the spherical particles to cause a brown discoloration such as Maillard reaction. Therefore, upon use with such medicinal agents, complicated tests are required for confirming the compatibility of the raw substances of the spherical particles with the medicinal agents.
Lactose has been focused on as a raw material of a spherical particle for pharmaceutical preparation, because it is less reactive with various medicinal agents and therefore has a low tendency to cause Maillard reaction with the medicinal agents. For example, Japanese Patent Application Laid-open No. 6-205959 discloses a lactose spherical particle and a method for producing it, in which the finished spherical particle comprising at least 95% lactose and has a longer diameter/shorter diameter ratio of 1.2 or lower, and as an aggregate, exerts a bulk density of 0.7 g/mL or larger and an angle of repose of 35 degree or less.